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Abstract: PO1453

Targeted Release Formulation Budesonide (Nefecon) Selectively Reduces Circulating Levels of Chemokines Critical to Immune Cell Trafficking to Peyer Patches in IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Molyneux, Karen, University of Leicester, Leicester, Leicestershire, United Kingdom
  • Wimbury, David Harry John, University of Leicester, Leicester, Leicestershire, United Kingdom
  • Bhachu, Jasraj Singh, University of Leicester, Leicester, Leicestershire, United Kingdom
  • Muto, Masahiro, Juntendo Daigaku, Bunkyo-ku, Tokyo, Japan
  • Stone, Andrew M., Stone Biostatistics ltd, Crewe, United Kingdom
  • Barratt, Jonathan, University of Leicester, Leicester, Leicestershire, United Kingdom
Background

Evidence supports a pivotal role of gut-derived chemokines in the direction of immune cell trafficking to the intestine in homeostatic and inflammatory conditions. It is well established that chemokines and their receptors control the influx of T cells and B cells into Peyer's patches (PP). T-cell homing to the PP depends on CCR7 and its ligands, CCL19 and CCL21, whereas B-cell homing to PP depends on the coordinated signaling of CCR7, CXCR4, CXCR5 and CCR6. The PP are believed to be a major source of the poorly O-galactosylated IgA1 in IgA nephropathy (IgAN). The therapeutic potential of targeting PP was demonstrated in the Phase 2 NEFIGAN trial (NCT01738035), which assessed the safety and efficacy of a novel targeted-release investigational formulation of budesonide (TRF-budesonide [Nefecon]), designed to deliver budesonide to the PP-rich distal ileum in patients with IgAN. The trial comprised a 6-month run-in, 9-month treatment, and 3-month follow-up phase: 49 patients received Nefecon 16 mg/day, 51 patients received Nefecon 8 mg/day and 50 patients received placebo. Nefecon 16 mg/day, added to optimized renin–angiotensin system blockade, reduced proteinuria and stabilized eGFR in patients with IgAN. This study investigated whether Nefecon treatment altered serum levels of chemokines.

Methods

Serum levels of a panel of 20 chemokines were measured by Luminex. Changes in log-transformed levels of each biomarker with treatment were compared by one-way ANCOVA. Significance was p<0.05.

Results

A significant, dose-dependent modulation in serum levels of key chemokines directing T and B cell trafficking to the intestine (CXCL5), and more specifically to the PP (CCL11, CCL19, CCL20) was seen with Nefecon, which reversed on cessation of Nefecon. These observations paralleled significant reductions in the levels of soluble CD23, CD27 and CD30, and are consistent with our previous reports describing a dose-dependent reduction in BAFF, soluble BCMA, TACI, IgA–IgG immune complexes, secretory IgA and galactose-deficient IgA levels with Nefecon.

Conclusion

Nefecon, which targets the PP-rich distal ileum, modulates key chemokine signals which direct immune cell trafficking to the intestine in IgAN.

Funding

  • Commercial Support